Vaginally administrable progesterone containing tablets and method for preparing the same

ABSTRACT

The present invention provides a method for preparing a tablet for the vaginal administration of progesterone for systemic use. The method comprises first mixing water with micronized progesterone, the total amount of water mixed with said micronized progesterone not exceeding the maximum wetting capacity of the micronized progesterone, drying the wetted, micronized progesterone; mixing the dry micronized progesterone with other pharmaceutically acceptable excipients or diluents; and; forming a tablet by direct compaction of the dry micronized progesterone. Tablets prepared by this method are also provided.

This application is a continuation of U.S. application Ser. No.11/039,062, filed on Jan. 12, 2005, which is a continuation of U.S.application Ser. No. 10/832,742, filed Apr. 26, 2004, which is acontinuation of U.S. application Ser. No. 09/856,417 filed Aug. 8, 2001,which was a U.S. national phase application under 35 U.S.C. §371 ofInternational Patent Application No. PCT/IL99/00619 filed on Nov. 17,1999, and claiming priority from Isreal Application 127129 filed on Nov.18, 1998. Each of these prior applications is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to the preparation of pharmaceutical compositionscontaining progesterone, in particular to compositions for vaginaldelivery of progesterone.

BACKGROUND OF THE INVENTION

Since its discovery in the 1950's, synthetic oral progesterone has beenused for a variety of gynecological conditions. However, androgenicactivity inherent in the synthetic compound precludes its liberal use inassisted reproductive technology (ART) because of the threat ofteratogenic effects.

Furthermore, synthetic progesterone used in hormonal replacement therapy(HRT) may partially reverse the estrogenic benefits on thecardiovascular system and lipoprotein metabolism (Lobo, Am. J. Obstet.Gynecol. 166 (1992), 1997-2004; Fahraeus et al., Eur. J. Clin. Invest.13 (1983), 447-453; Ottosson et al., Am. J. Obstet. Gynecol. 151 (1985),746-750; Knopp, Am. J. Obstet. Gynecol. 158 (1988), 1630-1643; Crook etal., 166 (1992) 950-954).

Natural progesterone is devoid of any androgenic activity that mightcompromise lipoprotein metabolism or induce teratogenicity. Moreover, itprobably has a direct beneficial effect on blood vessels (Jiang et al.,Eur. J. Pharmacol. 211 (1992), 163-167).

The major difficulty in utilizing natural progesterone is its route ofadministration. Oral intake is hampered by rapid and extensiveintestinal and liver metabolism, leading to poorly sustained serumlevels and low bioavailability (Adlercreutz et al., J. Steroid Biochem.13 (1980), 231-244; Arafat et al., Am. J. Obstet. Gynecol. 159 (1988),1203-1209; Whitehead et al., Brit. Med. J. 280 (1980), 825-827; Ottossonet al., Br. J. Obstet. Gynecol. 91 (1984), 11 11-1 119; Padwick et al.,Fertil. Steril. 46 (1986), 402-407; Nahoul et al., Maturitas 16 (1993),185-202; Nillus et al., Am. J. Obstet. Gynecol. 110 (1971), 470-477;Chakmakjian et al., J. Reprod. Med. 32 (1987), 443448). Intramuscularinjection assures reliable absorption, but is painful, can cause localirritation and cold abscesses (Devroey et al., Int. J. Fertil. 34(1989), 188-193), must be administered by trained medical personnel, andoften suffers from low patient compliance.

For these reasons, the vaginal route has become the most established wayin which to deliver natural progesterone. The progesterone is easilyadministered to the vagina, which has a large potential of absorption,and also avoids liver first-pass metabolism when delivered to thevagina.

Many vaginal formulations have been assayed, mostly as suppositories(Price et al., Fertil. Steril. 39 (1983), 490493; Norman et al., Fertil.Steril. 56 (1991), 1034-1039; Archer et al., Am. J. Obstet. Gynecol.,173 (1995), 471478), gelatin capsules (Devroey et al., Int. J. Fertil.34 (1989), 188-193; Smitz et al., Hum. Reprod. 2 (1992), 309-314; Mileset al., Fertil. Steril. 62 (1994), 485490), and recently as bio-adhesivegels (Fanchin et al., Obstet. Gynecol. 90 (1997), 396401; Ross et al.,Am. J. Obstet. Gynecol. 177 (1997), 937-941).

Although the suppositories are easily inserted, they melt at bodytemperature and lead to disturbing vaginal discharge. Oral gelatincapsule containing micronized progesterone have also been used vaginally(Devroey et al., Int. J. Fertil. 34 (1989), 188-193; Smitz et al., Hum.Reprod. 2 (1992), 309-314; Miles et al., Fertil. Steril. 62 (1994),485-490), but insertion of a small capsule high into the vagina isdifficult and large doses of 600 to 800 mg are needed to achieveadequate plasma concentration (Smitz et al., Hum. Reprod. 2 (1992),309-314; Miles et al., Fertil. Steril. 62 (1994), 485-490; Bourgain etal., Hum. Reprod. 5 (1990), 537-543).

U.S. Pat. Nos. 5,084,277 and 5,116,619, both to Greco et al., disclose aprocess for the preparation of a progesterone-containing tablet andtablets so prepared. The Greco et al. process involves wet granulationof progesterone into the tablets. As is well-known in the art, wetgranulation processes necessitate several steps in the formulation ofthe resulting tablets. These steps add considerably to the productioncosts of tablets produced by wet granulation methods, particularly incomparison to comparable “direct compaction” methods, in which thematerial of interest is tabletted while dry and which involve fewersteps than wet-granulation methods. Greco et al. employs a wetgranulation technique because commercially available progesterone hasbulk properties which render it unsuitable for direct compaction in theconcentrations necessary for use in ART (typically about 50-100 mgprogesterone per 1000 mg tablet). Greco gives no suggestion as to howone might be able to tablet progesterone via a direct-compaction method,which is economically more desirable.

The use of a wet granulation method in the preparation ofprogesterone-containing tablets also precludes incorporation of aneffervescent into the tablet. If the tablet is to be vaginallyadministered, incorporation of an effervescent would be helpful, sincethe effervescent would aid in the dissolution of the tablet andabsorption of the progesterone into the bloodstream.

SUMMARY OF THE INVENTION

The present invention seeks to provide a method for the production of atablet for the vaginal delivery of progesterone as well as tabletscontaining progesterone.

There is thus provided, in accordance with a preferred embodiment of theinvention, a method for preparing a tablet for the vaginaladministration of progesterone for systemic use, comprising the stepsof:

slowly mixing water with micronized progesterone, the total amount ofwater mixed with said micronized progesterone not exceeding the maximumwetting capacity of the micronized progesterone, whereby to obtainwetted micronized progesterone;

drying said wetted micronized progesterone to a humidity content ofsubstantially 0%, whereby to form substantially dry micronizedprogesterone;

mixing said substantially dry micronized progesterone with otherpharmaceutically acceptable excipients or diluents therefor; and

forming a tablet by direct compaction of said substantially drymicronized progesterone which has been mixed with said otherpharmaceutically acceptable excipients or diluents therefor.

There is also provided, in accordance with another preferred embodimentof the invention, a method for preparing a tablet for the vaginaladministration of progesterone for systemic use, comprising the stepsof:

slowly mixing water with micronized progesterone, the total amount ofwater mixed with said micronized progesterone not exceeding the maximumwetting capacity of the micronized progesterone, whereby to obtainwetted micronized progesterone;

drying said wetted micronized progesterone to a humidity content ofsubstantially 0%, whereby to form substantially dry micronizedprogesterone;

mixing said substantially dry micronized progesterone with otherpharmaceutically acceptable excipients or diluents therefor, includingan effervescent; and

forming a tablet by direct compaction of said substantially drymicronized progesterone which has been mixed with said otherpharmaceutically acceptable excipients or diluents therefor, includingan effervescent.

There is further provided, in accordance with another preferredembodiment of the invention, a method for preparing a tablet for thevaginal administration of progesterone for systemic use, comprising thesteps of:

slowly mixing water with micronized progesterone, the total amount ofwater mixed with said micronized progesterone does not exceed themaximum wetting capacity of the amount of micronized progesterone,whereby to obtain wetted micronized progesterone;

drying said wetted micronized progesterone to a humidity content ofsubstantially 0%, whereby to form substantially dry micronizedprogesterone;

sieving a first lubricant to obtain a sieved first lubricant;

mixing said substantially dry micronized progesterone with said sievedfirst lubricant and a material selected from a first filler or adisintegrant to form a first mixture;

mixing a binder which binds dry particles with said first mixture toform a second mixture;

intimately mixing an effervescent and a first quantity of a secondfiller to form a third mixture;

sieving said third mixture to obtain a sieved third mixture, and thenintimately mixing said sieved third mixture and said second mixture toform a fourth mixture;

intimately mixing the fourth mixture with a second quantity of saidsecond filler to form a fifth mixture;

sieving a second lubricant and a material selected from a saponificantor a third lubricant to obtain, respectively, sieved second lubricantand sieved third lubricant;

intimately mixing said sieved second lubricant and said sieved thirdlubricant with said fifth mixture to form a sixth mixture; and

tabletting said sixth mixture by direction compaction to form a tablet.

In a preferred embodiment of the invention, the amount of water mixedwith the micronized progesterone is between about 25 and 28 wt. % of theamount of micronized progesterone.

In another preferred embodiment of the invention, the water is added tothe micronized progesterone at rate of between about 6-9 ml per minute,at a mixing speed of between about 25-33.3 rpm.

In another preferred embodiment of the invention, the first lubricant issieved through sieves having a pore size of between about 400 and 450microns, preferably about 425 microns.

In another preferred embodiment of the invention, the third mixture issieved through sieves having a pore size of between about 400 and 450microns, preferably about 425 microns prior to mixing with the secondmixture.

In another preferred embodiment of the invention, said sieved secondlubricant and said sieved third lubricant are sieved through sieveshaving a pore size of between about 100 and 150 microns, preferably 125microns prior to mixing with said fifth mixture.

In one preferred embodiment of the invention, said drying of said wettedmicronized progesterone is done at a temperature of between about 55° C.and about 60° C.

In another preferred embodiment of the invention, all of said mixingsteps are carried out at a temperature of between about 15° C. and 30°C.

In one preferred embodiment of the invention, said first lubricant issilicon dioxide (colloidal anhydrous silica).

In another preferred embodiment of the invention, said material selectedfrom a first filler or a disintegrant is a starch exhibiting good flowproperties, such as cornstarch 1500 or other starches derived from corn(maize), potatoes or wheat, as are well known in the art.

In a preferred embodiment of the invention, the binder which binds dryparticles is polyvinylpyrrolidone (povidone), e.g. Povidone 30.

In another preferred embodiment of the invention, said second filler isderived from a natural source and is more preferably lactose or iscomposed principally of lactose (e.g. ludipress, which as is well knownin the art is a commercially available mixture of polyvinylpyrrolidoneand lactose).

In a preferred embodiment of the invention, said effervescent is amixture of a pharmaceutically acceptable carboxylic or dicarboxylicacid, such as adipic acid or tartaric acid, and a pharmaceuticallyacceptable salt of HCO₃ ⁻, such as sodium bicarbonate. Preferably theacid and bicarbonate are present in an amount providing a molar excessof −COOH groups.

In another preferred embodiment of the invention, said first portion andsaid second portion of said second filler are of generally the samesize.

In one preferred embodiment of the invention, the effervescent isprepared prior to said intimate mixing of said first portion of saidsecond filler with said effervescent. In another preferred embodiment ofthe invention, said effervescent is prepared in situ as part of saidintimate mixing of said first portion of said second filler with saideffervescent.

In a preferred embodiment of the invention, said intimate mixing of saidfirst portion of said second filler with said effervescent comprisesnon-intimately mixing said first portion of said second filler with saideffervescent and passing the resultant non-intimately mixed mixturethrough a sieve having an average pore size between about 400 and 450microns, preferably about 425 microns diameter to obtain said thirdmixture.

In a preferred embodiment of the invention, the effervescent comprisesbetween about 6 and 10 wt. %, preferably about 8 wt. % of the tablet.

In one preferred embodiment of the invention, said intimate mixing ofsaid second mixture with said third mixture to obtain said fourthmixture is accomplished by non-intimately mixing said second mixturewith said third mixture to obtain a non-intimately mixed mixture andsifting said non-intimately mixed mixture through a sieve having anaverage pore size between about 400 and 450 microns, preferably about425 microns diameter to obtain said fourth mixture.

In a preferred embodiment of the invention, said second lubricant isselected from magnesium stearate, talc, sodium lauryl sulfate, andphosphates known in the art to function as lubricants.

In another preferred embodiment of the invention, said material selectedfrom a saponificant or a third lubricant is sodium lauryl sulfate.

There is also provided in accordance with another preferred embodimentof the invention a tablet prepared by the steps of: slowly mixing waterwith micronized progesterone, the total amount of water mixed with saidmicronized progesterone not exceeding the maximum wetting capacity ofthe amount of micronized progesterone, whereby to obtain wettedmicronized progesterone; drying said wetted micronized progesterone to ahumidity content of substantially 0%, whereby to form substantially drymicronized progesterone; mixing said substantially dry micronizedprogesterone with other pharmaceutically acceptable excipients ordiluents therefor; and forming a tablet by direct compaction of saidsubstantially dry micronized progesterone which has been mixed with saidother pharmaceutically acceptable excipients or diluents therefor.

There is also provided in accordance with another preferred embodimentof the invention a tablet prepared by the steps of: slowly mixing waterwith micronized progesterone, the total amount of water mixed with saidmicronized progesterone not exceeding the maximum wetting capacity ofthe amount of micronized progesterone, whereby to obtain wettedmicronized progesterone; drying said wetted micronized progesterone to ahumidity content of substantially 0%, whereby to form substantially drymicronized progesterone; mixing said substantially dry micronizedprogesterone with other pharmaceutically acceptable excipients ordiluents therefor, including an effervescent; and forming a tablet bydirect compaction of said substantially dry micronized progesteronewhich has been mixed with said other pharmaceutically acceptableexcipients or diluents therefor, including an effervescent.

There is also provided in accordance with another preferred embodimentof the invention a tablet prepared by the steps of: slowly mixing waterwith micronized progesterone, the total amount of water mixed with saidmicronized progesterone not exceeding the maximum wetting capacity ofthe amount of micronized progesterone, whereby to obtain wettedmicronized progesterone; drying said wetted micronized progesterone to ahumidity content of substantially 0%, whereby to form substantially drymicronized progesterone; sieving a first lubricant to obtain a sievedfirst lubricant; mixing said substantially dry micronized progesteronewith said sieved first lubricant and a material selected from a firstfiller or a disintegrant to form a first mixture; mixing a binder whichbinds dry particles with said first mixture to form a second mixture;intimately mixing an effervescent and a first quantity of a secondfiller to form a third mixture; sieving said third mixture to obtain asieved third mixture, and then intimately mixing said sieved thirdmixture and said second mixture to form a fourth mixture; intimatelymixing the fourth mixture with a second quantity of said second fillerto form a fifth mixture; sieving a second lubricant and a materialselected from a saponificant or a third lubricant to obtain,respectively,.sieved second lubricant and sieved third lubricant;intimately mixing said sieved second lubricant and said sieved thirdlubricant with said fifth mixture to form a sixth mixture; andtabletting said sixth mixture by direction compaction to form a tablet.

There is also provided in accordance with a preferred embodiment of theinvention a tablet comprising between about 6 to 20 wt. % progesteroneand between about 5 to 12 wt. % effervescent. In a preferred embodimentof the invention, the tablet comprises between about 8 to 12 wt. %progesterone. In a preferred embodiment of the invention, the tabletcomprises between about 6 to 8 wt. % effervescent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention will be better understood through the followingillustrative and non-limitative description and examples of preferredembodiments of the invention.

EXAMPLE 1 Preparation of Tablets

Step 1: To 1000 g of micronized progesterone were added 280 g ofdistilled water, with mixing using a planetary mixer, over a period of30 minutes. After mixing, the wetted micronized progesterone was spreadon pans to thickness of about 4-5 mm, and the pans then placed in anoven at 58° C. The humidity was checked periodically using a humiditychecker. When the humidity of the micronized progesterone was reduced tosubstantially 0%, the dried micronized progesterone was either usedimmediately in step 2 as described below, or was stored in dry, sealedcontainers for later use in step 2.

Step 2: Colloidal anhydrous silica (Aerosil 380, 25 g) was sievedthrough a Russel sieve having pores of 425 micron size, and mixed for 10minutes with 1000 g of micronized progesterone from Step 1 and 2100 g ofmaize 1500 starch, using an Angelsman mixer at 32 RPM, to form MixtureA. At the end of the 10 minutes of mixing, 490 g of povidone 30 wereadded to Mixture A, and mixing was continued for another ten minutes, toprepare “Mixture B”.

Step 3: Lactose (Ludipress, BASF, 3800 g), adipic acid (570 g) andsodium bicarbonate (430 g) were mixed for 10 minutes at room temperatureusing an Angelsman mixer at 32 RPM. Following mixing, these ingredientswere sieved through a Russel sieve having pores of 425 microns to obtain“Mixture C”.

Step 4: Mixtures B and C were mixed for 10 minutes at room temperatureusing an Angelsman mixer at 32 RPM to obtain “Mixture D”.

Step 5: Mixture D (8415 g) was mixed with 3800 g of lactose (Ludipress)for 10 minutes at room temperature using an Angelsman mixer at 32 RPM,to obtain “Mixture E”.

Step 6: Magnesium stearate (230 g) and sodium lauryl sulfate (50 g) weresieved through a Russel sieve (pore size 125 microns). The sievedmagnesium stearate and sodium lauryl sulfate were then mixed for withmixture E for 20 minutes at room temperature using an Angelsman mixer,to obtain “Mixture F”.

Step 7: Tablets were obtained from mixture F by direct compaction usingan Eko Korsch Press. The amounts of ingredients listed in this exampleare suitable for production of 10,000 tablets each containing about 100mg progesterone.

EXAMPLE 2

Using the above process, tablets of 1187 mg to 1312 mg total weight,containing from 90 to 1 10 mg progesterone, were obtained.

EXAMPLE 3

The process described in Example 1 was modified by doubling the amountof filler (Ludipress) to obtain tablets containing on average 50 mgprogesterone.

EXAMPLE 4

The pharmacokinetics and clinical use of tablets prepared in accordancewith the invention were evaluated as follows: 50 healthy,post-menopausal women with intact uteri, 39 of whom had sufferedpremature menopause and 11 who were truly postmenopausal, all of whomwere undergoing hormone replacement therapy (HRT), submitted bloodsamples for determination of baseline profiles of hormones (progesteroneand other hormones) and other biochemicals (bilirubin, cholesterol,etc.). The blood samples were taken at 8 AM on the first day of theevaluation (day 0) in a fasting state, by intravenous indwellingcatheter which was introduced into the cubital vein. Non-estrogen primedpostmenopausal women were chosen in order to avoid confusion withendogenous progesterone secretion and estrogen influence on vaginalmucosa absorption (Villanueva et al., Fertil. Steril. 35 (1981),433437).

The women then self-administered the progesterone vaginal tablet using aplastic applicator and lay down for 20 minutes. Repeat blood samples forprogesterone concentration were withdrawn 0.5, 1, 2, 4, 6, 8, 10, 12 and24 hours after the vaginal insertion. Blood was allowed to clot at roomtemperature for 1 hour, after which the serum was separated bycentrifugation and stored at −20° C. until analysis.

To evaluate clinical use of the drug, the women were instructed toinsert tablets prepared in accordance with the present invention,containing the same dose as administered on day 0, twice daily startingon day 1, and to recline for 20 minutes after each insertion. On days 14and 30, blood samples for comparison with the baseline were drawn in themorning while the subjects were in a fasting state.

Of the 50 women who participated in the evaluation, 20 were allocatedtablets containing 50 mg progesterone, and the remainder of theparticipants received tablets containing 100 mg progesterone. Thebaseline details of the participants are summarized in Table I. TABLE ITablets containing Tablets containing 50 mg progesterone 100 mgprogesterone Total Median  43 ± 6.1 43.2 ± 7.9  43.3 ± 7.2  age (years)Age 28-53 28-55 28-55 range (years) Height 161.3 ± 8.6  161.6 ± 5.7 161.5 ± 6.9  (cm) Weight 67.1 ± 11.5 62.8 ± 13.1 64.5 ± 12.5 (kg) BMI25.9 ± 4.2  24.0 ± 4.4  24.8 ± 4.4  (kg/m²)Data are expressed as mean ± standard deviation unless otherwisespecified.Body mass index (BMI) was calculated as weight in kg divided by thesquare of height in meters.

A single vaginal application of a 50 mg progesterone-containing tabletprepared in accordance with the invention resulted in the rapid increaseof plasma progesterone concentration. The mean peak plasma level(T_(max)), mean elimination half-life (T_(1/2)), maximal serumconcentration (C_(max)), and AUC (area under the curve, i.e. totalamount of plasma progesterone observed) derived from the blood samplestaken on day 0 of the evaluation are summarized in Table II. TABLE IIProgesterone dose 50 mg (20 subjects) 100 mg (30 subjects) T_(max)(hour)  6.1 ± 2.63  6.4 ± 3.35 T_(1/2) (hours) 13.18 ± 1.3  13.7 ± 1.05C_(max) (nmol/liter) 20.43 ± 8.01   31.61 ± 12.62^(a) AUC(nmol/hour/liter) 154.15 ± 60.31   247.61 ± 123.04^(b)Values are mean ± standard deviation;^(a)P = 0.0004;^(b)P = 0.001.

As shown in Table III, after 14 and 30 days of continuous applicationtwice daily, the serum P levels were significantly higher compared tobaseline values on day 0. No statistically significant difference inplasma levels of follicle stimulating hormone, leutinizing hormone,estradiol, cortisol, dehydroepiendosterone sulfate, or aldosterone wereobserved in the study groups between baseline values and after continuedadministration of the tablets of the invention. Similarly, the plasmalevels of serum glutamic oxaloacetic transaminase, alkaline phosphatase,cholesterol, triglycerides, high density lipoprotein, low densitylipoprotein, and very low density lipoprotein did not changesignificantly between the baseline measurement and the measurements at14 and 30 days of twice-daily administration. TABLE III BloodProgesterone levels, nmol/liter Day sample Progesterone dose was taken50 mg (20 subjects) 100 mg (30 subjects) Day 0^(a) 1.05 ± 0.7  3.0 ± 2.4Day 14^(a) 17.48 ± 9.8^(b )  26.08 ± 13.96^(b) Day 30^(a) 17.38 ± 14.3921.42 ± 16.32^(a)P = 0.0001, significant difference between progesterone baselinevalues on day 0 compared to day 14 and day 30;^(b)P = 0.02.

EXAMPLE 5

The efficacy of tablets prepared in accordance with the presentinvention was compared with the efficacy of prior art tablets asfollows:

Thirteen healthy, postmenopausal women with intact uteri who wereundergoing hormonal replacement therapy (HRT) were given completemedical evaluation by history, physical and gynecological examination,and instructed to discontinue HRT two weeks prior to the comparativetrial.

Part A: Single-dose pharmacokinetics of micronized progesterone in theform of a gelatin capsule (Utrogestan, produced by Basins-Iscovesco,Paris, France). Participants received oral ethinyl estradiol (Estrofem,Novo-Nordisk, Denmark), 4 mg per day for 14 days. On day 14 at 8 AM, ina fasting state, an intravenous indwelling catheter was inserted intothe cubital vein and blood was drawn for baseline progesterone andestrogen levels. The women were then instructed to self-administer asingle gelatin capsule containing 100 mg of micronized progesterone highin the vagina. Repeat blood samples for progesterone concentrations weredrawn ½, 1, 2, 4, 6, 8, 10, 12 and 24 hours after the vaginal insertion.

Part B: Single-dose pharmacokinetics of micronized progesterone in theform of a vaginal tablet according to the present invention. After awashout period of 2 weeks, the same subjects as in Part A were againadministered 4 mg or ethinyl estradiol (Estrofein) for 14 days. On day14 the same procedure as recited in Part A was repeated, except thatthis time the women were instructed to insert 100 mg of progesterone inthe form of an effervescent tablet according to the present invention,using a plastic applicator. Blood samples for progesterone levels weredrawn at the same intervals as in Part A.

Samples were assayed using an Immulite enzyme immunoassay (DiagnosticProducts Corporation, Los Angeles, Calif.) to measure plasmaprogesterone (SI conversion factor 3.18; sensitivity 0.2 ng/ml (0.6nmol/L, inter- and intra-assay coefficients of variation precision<10%)) and estradiol (E₂) (SI conversion factor 3.67; sensitivity 12pg/ml (44 pmol/L, inter- and intra-assay coefficients of variationprecision <10%). The pharmacokinetic parameters calculated from theconcentration curve were compared between the two study groups by theWilcoxon 2-sample test, the Kruskal-Wallis test and by analysis ofvariance (ANOVA). Students T-test was used to compare estrogen levelsfor the two treatment parts.

Table IV summarizes the baseline details of the of the thirteen womenwho participated in the study of Example 5. TABLE IV Mean ± SD MedianMinimum Maximum Age (years) 52.2 ± 3.6  53 42 57 Weight (kg)   72 ± 15.470 46 100 Height (cm) 165.1 ± 6.5  165 155 178 BMI (kg/m²)  263 ± 4.7 25.7 19.1 34.2Data are expressed as mean ± standard deviation unless otherwisespecified.Body mass index (BMI) was calculated as weight in kg divided by thesquare of height in meters.

The mean peak plasma level (T_(max)), mean elimination half-life(T_(1/2)), maximal serum concentration (C_(max)), and AUC (area underthe curve, i.e. total amount of plasma progesterone observed) derivedfrom the blood samples taken on day 0 of the evaluation are summarizedin Table V. TABLE V Treatment Vaginal Tablet Gelatin Capsule Tmax(hours) 6.92 ± 3.12  6.23 ± 6.56^(b) T_(1/2) (hours) 16.39 ± 5.25  22.08± 16.5  C_(max) (nmol/l) 31.53 ± 9.15  23.85 ± 9.57^(a) AUC (nmol/h/l)379.99 ± 137.07 325.89 ± 167.78Values are mean ± standard deviation;^(a)P = 0.0472;^(b)Statistically significant difference of variance, P = 0.02.

A single dose of 100 mg micronized progesterone in the form of bothgelatin capsules and vaginally administrable tablets in accordance withthe present invention resulted in a similar rapid increase in plasmaprogesterone levels within 2.5-3 hours after administration. Thestatistically significant difference of variance between the two groupsindicates a more predictable T_(max) for the tablets of the presentinvention than for the prior art gelatin capsules.

It is to be understood that the amounts and proportions of ingredientsrecited in the foregoing examples are illustrative only, and that theseamounts and proportions may be varied within the scope of the invention.For example, the Example 1 the amount of effervescent recited is about 8wt. % of the tablets which are the final product of the processdescribed in Example 1. However, the effervescent may be omitted in thepractice of the invention, or it may be included in an amount of up toabout 12 wt. % of the tablet. Preferably the effervescent constitutesbetween about 5-12 wt. %, more preferably between about 6-8 wt. % of thetablet. Similarly, progesterone may constitute up to about 20 wt. % ofthe tablet, preferably between about 6-20 wvt.%, more preferably betweenabout 8-12 wt. % of the tablet.

It will be appreciated that various features of the invention which are,for clarity, described in the contexts of separate embodiments may alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment may also be provided separately or in anysuitable subcombination.

It will also be appreciated by persons skilled in the art that thepresent invention is not limited by what has been particularly shown anddescribed hereinabove. Rather the scope of the invention is defined onlyby the claims which follow:

1. A method for preparing a tablet for the vaginal administration of: progesterone for systemic use, comprising the steps of: (i) preparing a mixture consisting of water and micronized progesterone to obtain wetted micronized progesterone; (ii) drying the wetted micronized progesterone to obtain dry micronized progesterone; (iii) mixing the dried micronized progesterone with at least one pharmaceutically acceptable excipient or diluent to form a second mixture; and (iv) forming a tablet by direct compaction of the second mixture.
 2. The method of claim 1, wherein step (iii) comprises mixing the dry micronized progesterone with (a) a pharmaceutically acceptable non-effervescent excipient or diluent; and (b) an effervescent.
 3. The method of claim 2, wherein the micronized progesterone is present in from about 6% to about 20% by weight of the tablet.
 4. The method of claim 2, wherein the micronized progesterone is present in from about 8% to about 12% by weight of the tablet.
 5. The method of claim 2, wherein the effervescent is a mixture of a pharmaceutically acceptable carboxylic or dicarboxylic acid and a pharmaceutically acceptable salt of HCO₃ ⁻.
 6. The method of claim 5, wherein the pharmaceutically acceptable salt of HCO₃ ⁻ is sodium bicarbonate.
 7. The method of claim 2, wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid is adipic acid or tartaric acid.
 8. The method of claim 7, wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid and said bicarbonate are present in an amount providing a molar excess of —COOH groups.
 9. The method of claim 2, wherein the effervescent comprises a mixture ofadipic acid and sodium bicarbonate.
 10. The method of claim 2, wherein the effervescent comprises between about 5% and about 12% by weight of the tablet.
 11. The method of claim 10, wherein the effervescent comprises about 8% by weight of the tablet.
 12. The method of claim 2, wherein the amount of water mixed with the micronized progesterone is between about 25% and 28% by weight of the amount of micronized progesterone.
 13. The method of claim 12, wherein the amount of water mixed with the micronized progesterone is about 28% by weight of the amount of micronized progesterone.
 14. The method according to claim 2, wherein the dried micronized
 15. The method according to claim 2, wherein step (iii) comprises: (i) sieving a first lubricant to obtain a sieved first lubricant; (ii) mixing the dry micronized progesterone with the sieved first lubricant and a material selected from a first filler or a disintegrant to form a first mixture; (iii) mixing a binder which binds dry particles with the first mixture to form a second mixture; (iv) intimately mixing the effervescent and a first quantity of a second filler to form a third mixture; (v) sieving the third mixture to obtain a sieved third mixture, and then intimately mixing the sieved third mixture and the second mixture to form a fourth mixture; (vi) intimately mixing the fourth mixture with a second quantity of the second filler to form a fifth mixture; (vii) sieving a second lubricant and a material selected from a saponificant or a third lubricant to obtain, respectively, sieved second lubricant and sieved third lubricant; and (viii) intimately mixing the sieved second lubricant and said sieved third lubricant with said fifth mixture to form a sixth mixture.
 16. The method of claim 15, wherein said first lubricant is silicon dioxide.
 17. A method according to claim 15, wherein the material in step (ii) is a disintegrant, and wherein the disintegrant is a starch derived from corn, potatoes or wheat.
 18. The method of claim 17, wherein said starch is cornstarch.
 19. The method of claim 15, wherein the binder is polyvinylpyrrolidone.
 20. The method of claim 15, wherein the second filler is selected from lactose or a composition consisting essentially of lactose.
 21. A method according to claim 15, wherein the second lubricant is selected from the group consisting of magnesium stearate, talc, sodium lauryl sulfate, and phosphates.
 22. The method of claim 15, wherein the material selected from a saponificant or a third lubricant in step (vii) is sodium lauryl sulfate.
 23. A method for preparing a tablet useful for vaginal administration of progesterone which comprises (i) mixing water with micronized progesterone, prior to adding any other ingredients, to obtain wetted micronized progesterone; (ii) drying the wetted micronized progesterone; (iii) mixing a pharmaceutically acceptable excipient or diluent with the micronized progesterone after the drying step to form a tabletting mixture; and (iv) directly compacting the tabletting mixture to form the tablet.
 24. The method of claim 23 for preparing a tablet for the vaginal administration of progesterone for systemic use, wherein the mixture in step (i) consists essentially of water and micronized progesterone.
 25. A method for preparing a tablet for the vaginal administration of progesterone for systemic use, comprising the following sequential steps: (i) first mixing water with micronized progesterone, in the absence of a pharmaceutically acceptable excipient or diluent, to obtain wetted micronized progesterone; (ii) drying said wetted micronized progesterone to form dry micronized progesterone; (iii) mixing said dry micronized progesterone with (a) a pharmaceutically acceptable non effervescent excipient or diluent; and (b) an effervescent to form a mixture; and (iv) forming a tablet by direct compaction of said mixture. 